Monodispersed DOTA-PEG-conjugated anti-TAG-72 diabody has low kidney uptake and high tumor-to-blood ratios resulting in improved 64Cu PET.
Monodispersed DOTA-PEG-conjugated anti-TAG-72 diabody has low kidney uptake and high tumor-to-blood ratios resulting in improved 64Cu PET.
复制标题
DOI：
10.2967/jnumed.109.074153
复制
发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Shively JE
中科院分区：
文献类型：
--
作者：
Li L;Turatti F;Crow D;Bading JR;Anderson AL;Poku E;Yazaki PJ;Williams LE;Tamvakis D;Sanders P;Leong D;Raubitschek A;Hudson PJ;Colcher D;Shively JE
双抗体是单链抗体片段（scFv）的非共价二聚体，其保留完整IgG的亲合力，但具有比完整IgG更有利的血液清除率。放射性金属提供广泛的半衰期和发射，以满足成像和治疗要求，并提供螯合物-抗体缀合物的简易标记。然而，由于它们在肾脏中的高保留和代谢，放射性金属标记的双抗体的使用对于成像和治疗都可能是有问题的。先前已经显示111 In-DOTA-PEG 3400-抗CEA-双抗体具有与非PEG化双抗体类似的高肿瘤摄取和保留以及少于50%的肾摄取和保留，我们合成了抗TAG-72-双抗体的类似衍生物。我们还将多分散的PEG 3400的分子尺寸减小为单分散的PEG 27和PEG 12（标称质量分别为1188和528）。我们进行了生物分布的DOTA共轭物放射性标记的125 I，111 In，或64铜在荷瘤裸鼠。将PEG 3400添加至双抗体将肾摄取降低至与用放射性金属标记的完整IgG获得的水平相当的水平（约10%ID/g）。PEG 27和PEG 12双抗体缀合物还显示低肾摄取，而不降低肿瘤摄取或肿瘤与血液的比率。当用64 Cu放射性标记时，DOTA-PEG 12-和PEG 27-双抗体缀合物给出无胸腺小鼠中结肠癌异种移植物的高对比度PET图像。PEG化的双抗体可以是用于将放射性核素和其他试剂递送至肿瘤的有价值的平台。
Diabodies are non-covalent dimers of single chain antibody fragments (scFvs) that retain the avidity of intact IgG but have more favorable blood clearance than intact IgGs. Radiometals offer a wide range of half lives and emissions for matching imaging and therapy requirements and provide facile labeling of chelate-antibody conjugates. However, due to their high retention and metabolism in the kidney, use of radiometal labeled diabodies can be problematic for both imaging and therapy. Having previously shown that 111In-DOTA-PEG3400-anti-CEA-diabody has similarly high tumor uptake and retention and less than 50% as much kidney uptake and retention as non-PEGylated diabody, we synthesized a similar derivative for an anti-TAG-72-diabody. We also reduced the molecular size of the polydispersed PEG3400 to monodispersed PEG27 and PEG12 (nominal masses of 1188 and 528, respectively). We performed biodistributions of their DOTA conjugates radiolabeled with 125I, 111In, or 64Cu in tumor bearing athymic mice. Addition of PEG3400 to the diabody reduced kidney uptake to a level (≈10 %ID/g) comparable to that obtained with radiometal labeled intact IgG. The PEG27 and PEG12 diabody conjugates also demonstrated low kidney uptake without reduction of tumor uptake or tumor to blood ratios. When radiolabeled with 64Cu, the DOTA-PEG12- and PEG27-diabody conjugates gave high contrast PET images of colon cancer xenografts in athymic mice. PEGylated diabodies may be a valuable platform for delivery of radionuclides and other agents to tumors.
登录
查看更多内容
DOI：
10.1007/s00259-004-1664-0
发表时间：
2005-03-01
影响因子：
9.1
作者：
Chauhan, SC;Jain, M;Batra, SK
通讯作者：
Batra, SK
影响因子：
4.7
作者：
Tsai, SW;Li, L;Shively, JE
通讯作者：
Shively, JE
影响因子：
3.9
作者：
Gangopadhyay, A;Thomas, P
通讯作者：
Thomas, P
影响因子：
11.2
作者：
Olafsen, T;Kenanova, VE;Wu, AM
通讯作者：
Wu, AM
影响因子：
4.7
作者：
Li, L;Tsai, SW;Shively, JE
通讯作者：
Shively, JE